Men typically have higher blood pressure (BP) than premenopausal women. Following menopause, when estradiol levels decrease, BP increases sometimes to levels higher than in men. In hypertensive men and women of all ages, there are sub-populations that develop salt-sensitivity of BP. Women have increased prevalence of salt sensitivity of BP following menopause, and treatment of postmenopausal women with 17beta-estradiol reduced salt-sensitivity of BP in some studies. Although these data suggest that sex steroids can modulate BP, the mechanisms responsible for the sex differences in BP control are not clear. The male Dahl salt-sensitive (DS) rat exhibits an exaggerated pressor response to high salt in comparison with females. Castration attenuates this response, whereas ovariectomy (ovx) exacerbates the pressor response. How sex steroids modulate the gender differences in the pressor response to high salt diet has not been elucidated. Our overall hypothesis is that in DS, either directly or indirectly, androgens promote and estrogens protect against the shift to the right in the pressure-natiuresis relationship in response to high salt diet. Specifically, we hypothesize that in male DS on high salt, androgens upregulate renal cortical endothelin (ET)/ETA receptor and oxidative stress. Conversely, in female DS, estradiol protects against the salt-induced increase in BP by attenuating endothelin/ETA upregulation and oxidative stress. The following hypotheses will be tested using an integrative approach of physiological, biochemical and molecular methods in these specific aims: 1) the sex differences in the response to salt in DS are mediated in part via androgen-induced upregulation of the renal cortical endothelin/ETA system, while estradiol attenuates the renal endothelin/ETA system;2) the sex differences in the response to salt in DS are mediated in part via androgen-induced oxidative stress, either directly or via activation of the endothelin system, with upregulation of NADPH oxidase, while estradiol attenuates oxidative stress and NADPH oxidase expression.